Source:http://linkedlifedata.com/resource/pubmed/id/15456758
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
50
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| pubmed:dateCreated |
2004-12-6
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| pubmed:databankReference | |
| pubmed:abstractText |
Platelet-activating factor (PAF) is an important mediator of cell loss following diverse pathophysiological challenges, but the manner in which PAF transduces death is not clear. Both PAF receptor-dependent and -independent pathways are implicated. In this study, we show that extracellular PAF can be internalized through PAF receptor-independent mechanisms and can initiate caspase-3-dependent apoptosis when cytosolic concentrations are elevated by approximately 15 pM/cell for 60 min. Reducing cytosolic PAF to less than 10 pM/cell terminates apoptotic signaling. By pharmacological inhibition of PAF acetylhydrolase I and II (PAF-AH) activity and down-regulation of PAF-AH I catalytic subunits by RNA interference, we show that the PAF receptor-independent death pathway is regulated by PAF-AH I and, to a lesser extent, by PAF-AH II. Moreover, the anti-apoptotic actions of PAF-AH I are subunit-specific. PAF-AH I alpha1 regulates intracellular PAF concentrations under normal physiological conditions, but expression is not sufficient to reduce an acute rise in intracellular PAF levels. PAF-AH I alpha2 expression is induced when cells are deprived of serum or exposed to apoptogenic PAF concentrations limiting the duration of pathological cytosolic PAF accumulation. To block PAF receptor-independent death pathway, we screened a panel of PAF antagonists (CV-3988, CV-6209, BN 52021, and FR 49175). BN 52021 and FR 49175 accelerated PAF hydrolysis and inhibited PAF-mediated caspase 3 activation. Both antagonists act indirectly to promote PAF-AH I alpha2 homodimer activity by reducing PAF-AH I alpha1 expression. These findings identify PAF-AH I alpha2 as a potent anti-apoptotic protein and describe a new means of pharmacologically targeting PAF-AH I to inhibit PAF-mediated cell death.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/1-Alkyl-2-acetylglycerophosphocholin...,
http://linkedlifedata.com/resource/pubmed/chemical/Diterpenes,
http://linkedlifedata.com/resource/pubmed/chemical/Ginkgolides,
http://linkedlifedata.com/resource/pubmed/chemical/Gliotoxin,
http://linkedlifedata.com/resource/pubmed/chemical/Lactones,
http://linkedlifedata.com/resource/pubmed/chemical/Platelet Activating Factor,
http://linkedlifedata.com/resource/pubmed/chemical/Platelet Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Subunits,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, G-Protein-Coupled,
http://linkedlifedata.com/resource/pubmed/chemical/bisdethiobis(methylthio)gliotoxin,
http://linkedlifedata.com/resource/pubmed/chemical/ginkgolide B,
http://linkedlifedata.com/resource/pubmed/chemical/platelet activating factor receptor
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| pubmed:status |
MEDLINE
|
| pubmed:month |
Dec
|
| pubmed:issn |
0021-9258
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| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
10
|
| pubmed:volume |
279
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
52425-36
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| pubmed:dateRevised |
2006-11-15
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| pubmed:meshHeading |
pubmed-meshheading:15456758-1-Alkyl-2-acetylglycerophosphocholine Esterase,
pubmed-meshheading:15456758-Animals,
pubmed-meshheading:15456758-Apoptosis,
pubmed-meshheading:15456758-Base Sequence,
pubmed-meshheading:15456758-Brain,
pubmed-meshheading:15456758-Catalytic Domain,
pubmed-meshheading:15456758-Diterpenes,
pubmed-meshheading:15456758-Ginkgolides,
pubmed-meshheading:15456758-Gliotoxin,
pubmed-meshheading:15456758-Lactones,
pubmed-meshheading:15456758-Mice,
pubmed-meshheading:15456758-Mice, Inbred C57BL,
pubmed-meshheading:15456758-Molecular Sequence Data,
pubmed-meshheading:15456758-PC12 Cells,
pubmed-meshheading:15456758-Platelet Activating Factor,
pubmed-meshheading:15456758-Platelet Membrane Glycoproteins,
pubmed-meshheading:15456758-Protein Subunits,
pubmed-meshheading:15456758-RNA, Small Interfering,
pubmed-meshheading:15456758-RNA Interference,
pubmed-meshheading:15456758-Rats,
pubmed-meshheading:15456758-Receptors, G-Protein-Coupled,
pubmed-meshheading:15456758-Signal Transduction
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| pubmed:year |
2004
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| pubmed:articleTitle |
Anti-apoptotic actions of the platelet-activating factor acetylhydrolase I alpha2 catalytic subunit.
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| pubmed:affiliation |
Neural Regeneration Laboratory, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|